CHLORDIAZEPOXIDE HYDROCHLORIDE
Clinical safety rating: avoid
CNS depressants including alcohol and opioids increase sedation risk Abrupt discontinuation can cause withdrawal symptoms.
Binds to benzodiazepine site on GABA-A receptor, enhancing GABA-mediated chloride ion influx, leading to neuronal hyperpolarization and reduced excitability.
| Metabolism | Hepatic via CYP3A4 and CYP2C19; active metabolite desmethylchlordiazepoxide; also metabolized to demoxepam and nordazepam. |
| Excretion | Renal: approximately 50-60% as metabolites (mainly conjugated forms), with less than 1% unchanged. Fecal: minor, about 10%. Biliary excretion contributes to enterohepatic circulation. |
| Half-life | Terminal elimination half-life: 6.6 to 28 hours (parent drug); clinically, duration of effect may be prolonged due to active metabolite nordazepam (half-life 30-100 hours), especially in elderly or hepatic impairment. |
| Protein binding | 96-98% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | 3.4 L/kg (range 2-5 L/kg), indicating extensive tissue distribution, particularly in adipose tissue and brain. |
| Bioavailability | Oral: approximately 80-100% (mean ~86%). Intramuscular: incomplete and erratic, 50-70% (not recommended). |
| Onset of Action | Intravenous: 1-5 minutes. Oral: 30-60 minutes for sedation; slower for anxiolytic effect (1-2 hours). Intramuscular: absorption erratic, onset 15-30 minutes but variable. |
| Duration of Action | Intravenous: 1-3 hours for acute sedation; oral anxiolytic effect persists 4-8 hours. Duration can extend due to active metabolites; accumulation possible with repeated dosing. |
Oral: 5-25 mg 3-4 times daily, up to 100 mg/day in severe anxiety; IM/IV: 50-100 mg initially, then 25-50 mg 3-4 times daily.
| Dosage form | CAPSULE |
| Renal impairment | No specific guidelines; use caution in severe impairment (CrCl <10 mL/min). Avoid in renal failure. |
| Liver impairment | Child-Pugh A: 50% of normal dose; Child-Pugh B: 25% of normal dose; Child-Pugh C: not recommended. |
| Pediatric use | Children >6 years: 5 mg 2-4 times daily, maximum 10 mg 2-4 times daily; not recommended <6 years. |
| Geriatric use | Start at 5 mg 1-2 times daily, titrate slowly; maximum 10 mg 2 times daily due to increased sensitivity and fall risk. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and opioids increase sedation risk Abrupt discontinuation can cause withdrawal symptoms.
| FDA category | Positive |
| Breastfeeding | Chlordiazepoxide and its active metabolite nordiazepam are excreted into breast milk. M/P ratio for chlordiazepoxide is approximately 0.37. Infant exposure is dose-dependent; potential for sedation and withdrawal upon weaning. Use with caution; consider alternative if prolonged therapy needed. |
| Teratogenic Risk |
■ FDA Black Box Warning
Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death. Avoid co-prescription unless no alternatives.
| Common Effects | alcohol withdrawal |
| Serious Effects |
["Hypersensitivity to chlordiazepoxide or other benzodiazepines","Narrow-angle glaucoma","Myasthenia gravis","Severe respiratory insufficiency","Sleep apnea syndrome","Concomitant use with opioids (unless no alternatives)"]
| Precautions | ["Risk of dependence and withdrawal reactions","Concomitant use with CNS depressants increases sedation","Hepatic impairment may prolong effects","Elderly patients more sensitive to adverse effects","Paradoxical reactions (e.g., excitability) may occur"] |
| Food/Dietary | Avoid alcohol and grapefruit juice. Alcohol potentiates CNS depression; grapefruit juice inhibits CYP3A4 metabolism, increasing chlordiazepoxide and metabolite levels. Caffeine may reduce sedative effects; consistent caffeine use is recommended if continued. No restrictions on other foods. |
Loading safety data…
| Chlordiazepoxide crosses the placenta. First trimester exposure: Increased risk of oral clefts (meta-analysis RR 1.79). Second/third trimester: Risk of neonatal withdrawal (irritability, hypertonia, tremors) and floppy infant syndrome (hypotonia, respiratory depression, poor feeding) especially with chronic use. Avoid use in pregnancy unless benefit outweighs risk. |
| Fetal Monitoring | Monitor maternal vital signs and level of consciousness due to CNS depression risk. Assess fetal heart rate and uterine activity if used near term. Evaluate neonate for respiratory depression, hypotonia, and feeding difficulties after delivery, especially with chronic maternal dosing. |
| Fertility Effects | No systematic evidence of adverse effects on human fertility. Animal studies show no impairment of fertility at clinical doses. However, potential for hormonal disturbances with chronic high-dose use due to CNS effects. |
| Clinical Pearls | Chlordiazepoxide has a slower onset compared to diazepam due to lower lipid solubility; preferred for acute alcohol withdrawal to reduce seizure risk. Long half-life (5-30 hours) with an active metabolite (nordazepam) extending effects, necessitating caution in elderly and hepatic impairment. Avoid IM injection due to erratic absorption; administer IV slowly no faster than 50 mg/min to avoid respiratory depression. Note paradoxical disinhibition in some patients, especially children and elderly. Withdrawal from chlordiazepoxide can be severe (seizures, delirium); taper gradually over weeks to months after prolonged use. |
| Patient Advice | Avoid alcohol and other CNS depressants; may cause severe sedation or respiratory depression. · Do not drive or operate machinery until you know how this medication affects you. · Take exactly as prescribed; abrupt discontinuation can cause withdrawal symptoms including seizures. · Inform your doctor if you are pregnant, breastfeeding, or have liver disease. · May cause drowsiness, dizziness, or unsteadiness; rise slowly from sitting or lying position. · Avoid grapefruit juice as it may increase chlordiazepoxide levels. · Do not increase dose or frequency without consulting your doctor. · Keep out of reach of children; this medication can be habit-forming. |